Obesity affects 1 in 3 adults in the United States. Among the health problems associated with obesity is a higher risk for the development of chronic kidney disease (CKD) and for CKD progression. The association between obesity and CKD persists even after statistical adjustment for diabetes and hypertension, which are known CKD risk factors that are often present in people with obesity. This suggests that obesity itself, independent of other comorbid conditions, contributes to CKD. The pathogenic mechanisms linking obesity to CKD are incompletely understood. This project tests a highly innovative model integrating existing knowledge with new findings in multiple areas of human pathophysiology and microbial biology. This model is divided into three hypotheses that are conceptually interrelated but independently testable: 1. Obesity-associated alterations in the microbes that normally reside in the intestine lead to excess acid production by microbial metabolism. This excess acid is absorbed by the intestine and then excreted by the kidney, as the kidney is tasked with preventing excess acid from accumulating in the body. 2. Excess acid excretion by the kidney mandates increased glutamine metabolism to generate ammonium (important for acid excretion), but since the resulting glutamine metabolites are used in the cell to generate energy, this reduces the utilization of other energy substrates such as fatty acids by substrate competition. In turn, this makes more fatty acids available for entry into alternative metabolic pathways, resulting in renal lipid accumulation (steatosis) and toxic effects (lipotoxicity). 3. Finally, excess acid excretion contributes to CKD progression via decreased fatty acid utilization, steatosis and lipotoxicity, and this effect is made worse by the fact that kidney lipid metabolism is already disturbed in obesity. These hypotheses will be tested using a combination of in vitro, animal and human studies employing some of the latest technologies in magnetic resonance imaging, nuclear magnetic resonance spectroscopy, germ-free mouse research and targeted mouse genetics, combined with classical physiology and biochemistry. In summary, this project aims to advance the field by testing previously unexplored, but clear and plausible hypotheses linking obesity, intestinal microbes, increased acid excretion by the kidney, kidney lipid abnormalities, and CKD progression. This project will generate new knowledge that will form the basis for new logical interventions to prevent CKD progression. This is in keeping with the overarching mission of the NIH of improving human health through science.